Although chronic cyclosporine or FK506-based immunosuppression has dramatically improved organ allograft survival, the vast majority of patients develop impaired graft function or even graft failure owing to chronic rejection. Therefore, the ultimate goal - to radically improve graft survival -must be achieved by induction of tolerance of organ allografts without the need for continuous drug therapy. Our results have demonstrated that designed donor/recipient histocompatibility proteins may induce tolerance. Tolerant recipients exhibited selective activation of interleukin (IL)-4-producing Th2 cells, which displayed reduced signaling through the intracellular molecules ERK2, NF-kappaB AP-1, Jak3, and Stat5. We propose that tolerance induction by tolerogenic protein depends upon the expansion of a unique regulatory Th2 with an IL-4-driven Jak3/Stat5/Stat6 feedback loop. In fact, we intend to show the existence of two types of Th2 cells: namely, regulatory Th2 with IL-4-driven Stat5 and Stat6 and classical Th2 with IL-4-driven Stat6 but not Stat5. Furthermore, we plan to demonstrate that these subsets are modulated by a family of Jak/Stat regulatory molecules, including supressors of cytokine signaling (SOCS)-1, SOCS-2, SOCS-3, cytokine inducible SH-2 containing protein (CIS)-1, and tyrosine phosphatase SH2 containing protein (Shp)-1. This study may provide evidence that tolerogenic vaccines induce potent Jak/Stat regulatory proteins, which are instrumental in tolerance induction.